Model Complexities: Impacts of Inter-Individual Variability and Multicellularity on Modeling Inhaled Chemical Exposures In Vitro
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Inhaled chemical exposures are a ubiquitous aspect of daily life around the world. While there are thousands of inhalable chemicals and materials in use, there are few, or often no, data available to evaluate potential hazards posed by most of these agents. Traditional chemical decision making has relied on in vivo animal studies; however, the cost and duration of these studies makes their use to inform decision making for the large number of data poor chemicals, and an exponentially larger number of mixtures and repeated exposure scenarios, intractable. Further, the extrapolation from exposure effects in animals to human health outcomes is limited by concerns regarding the comparability of humans and surrogate animal species, especially in the context of inhalation exposures. To increase the throughput and human relevance of toxicity testing the National Research Council recommended the advancement of “new approach methodologies” (NAMs) that focus on computational biology and human-derived cell culture models. Differentiated primary cell-based multi-cellular in vitro models of the human respiratory tract recapitulate key features of in vivo human biology and provide novel opportunities to advance our assessment of the effects of inhaled chemical exposures on human health. One such opportunity is the incorporation of inter-individual variability, which cannot be well represented by traditional models including inbred animal strains and isogenic cell lines. Data will be presented examining the role of inter-individual variability on a broad range of in vivo physiology-relevant endpoints in response to model gases and how this information can inform in vitro approaches to chemical testing to ensure the protection of the population at large, as well as sensitive and susceptible sub-populations. Further, the incorporation of additional cell types into in vitro systems to recapitulate the in vivo tissue microenvironment increases the physiological relevance of in vitro respiratory tract models and allows for a more comprehensive evaluation of the potential effects of inhaled agents. Data will be presented demonstrating that exposure of a bronchial epithelial barrier causes effects in underlying lung fibroblasts (i.e., “trans-epithelial” effects) in a multi-cellular model of the tracheobronchial epithelium and discuss considerations facing the use of these systems for inhaled chemical decision making. Overall, this presentation will provide novel insight on these opportunities and challenges for the use of primary cell-based multi-cellular in vitro systems for inhalation toxicology and in chemical decision making in general. This abstract does not reflect EPA policy.